DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 06/02/2022, is a 371 filing of PCT/US2020/063444, filed 12/04/2020, which claims domestic benefit to US provisional application 62/945,053, filed 12/06/2019.
Status of Application, Amendments, and/or Claims
Applicant’s response of 08/07/2026 is acknowledged. No claims are amended or new. Claims 7, 9, 13, 15-18, 20, 22, 25-28, 30, 32-33, 36-37, 40-42, 44-48, 52-54, and 56-57 are cancelled. Claims 1-6, 8, 10-12, 14, 19, 21, 23-24, 29, 31, 34-35, 38-39, 43, 49-51, 55, and 58-59 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/07/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Rejections
In the office action of 04/09/2026, the claims were rejected under nonstatutory double patenting over copending application 17/638,147. The copending application was abandoned on 04/29/2026 rendering the rejection moot and the rejection is withdrawn.
The following grounds of rejections are maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 8, 10-12, 21, 23-24, 29, 31, 34-35, 38-39, 43, 49-51, 55, and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over Nagaya, T., et al (2017) Near infrared photoimmunotherapy with avelumab, an anti-programed death-ligand 1 (PD-L1) antibody Oncotarget 8(5); 8807-8817 in view of US 2018/0250405 A1 (Biel, M., et al) 6 SEPT 2018.
Nagaya teaches that near infrared-photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC) and that programmed death protein-1 ligand (PD-L1) is emerging as a molecular target. Nagaya describes the efficacy of NIR-PIT using fully human IgG1 anti-PD-L1 monoclonal antibody, avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441, papillary adenocarcinoma of lung, cell line (abstract).
Nagaya teaches that several monoclonal antibodies directed against PD-L1 and PD-1 have demonstrated clinical benefit in patients with melanoma, Hodgkin’s lymphoma, lung, and bladder carcinomas, and several other tumor types. The mode of action of these antibodies is to inhibit the interaction between PD-1 on immune cells and PD-L1 on tumor cells, thus reducing or eliminating immunosuppressive signals and leading to enhanced immune cell activation. Avelumab (MSB0010718C) is a fully human IgG1 anti-PD-L1 antibody with potential ADCC properties that, at the time publication, was currently in clinical trial. Despite promising early results, the treatment had not been successful in all patients (page 8807, paragraph bridging columns).
NIR-PIT is a newly developed cancer treatment that employs a targeted monoclonal antibody-photo-absorber conjugate (APC). The photo-absorber, IRDye700DX, or IR700, silica-phthalocyanine dye, is a highly hydrophilic dye, differentiating it from prior hydrophobic dyes used in photodynamic therapy. At the time of publication, the first-in-human phase 1 trial of NIR-RIT with the APC targeting epidermal growth factor receptor (EGFR) in patients with inoperable head and neck cancer was underway (page 8808, left column, paragraph 1).
Nagaya teaches that NIR-PIT had been shown to be effective with a variety of different antibodies and teaches an investigation of avelumab-IR700 as a candidate APC for NIR-PIT. Using a PD-L1 expressing papillary adenocarcinoma of lung cell line, H441, in vitro tumor binding, in vivo tumor accumulation and intratumoral distribution were evaluated. Avelumab-IR700 was then studied in vitro and in a tumor-bearing mouse model in vivo (page 8808, paragraph bridging columns).
In the studies performed by Nagaya, 100 μg of avelumab-IR700 was administered via i.v. and NIR light was administered at 50 J/cm2 on day 1 after injection and 100 J/cm2 on day 2 after injection with a 700 nm fluorescence channel (page 8814, paragraph bridging columns).
Nagaya teaches that treatment with the conjugate and light exposures resulted in rapid cell death in vitro and tumor growth reduction and survival improvement in vivo (page 8812, left column, paragraph 1).
Nagaya concludes that NIR-PIT using avelumab-IR700 can induce significant therapeutic responses after only a single injection of the conjugate and two light exposures in a PD-L1 expressing animal tumor model. Thus, NIR-PIT utilizing PD-L1 as the targeting antigen for the APC might be successful in treating cancers that have not previously responded to the naked antibody alone (paragraph bridging pages 8812-8813).
Nagaya differs from the instantly claimed invention in that, in the study performed by Nagaya, two, not one, light exposures were used.
US’405 teaches a phthalocyanine dye, for example IR700, linked to an immune modulating agent that binds to an immunosuppressive molecule expressed on tumor cells, for example an immune checkpoint molecule, including PD-L1. US’405 further teaches that the immune checkpoint inhibitor is an antibody or antigen binding antibody fragment that binds PD-L1. Exemplary anti-PD-L1 antibodies include, but are not limited to, BMS-935559, MEDI4736, MPDL3280A, and MSB0010718C (which is avelumab as evidenced by Nagaya). US’405 teaches that the conjugates can be used in methods of photoimmunotherapy, for example, by irradiation with light at a wavelength sufficient to activate the dye (page 45, [0493]). US’405 further exemplifies an anti-PD-L1-IRDye 700DX conjugate (page 77, [1066]).
US’405 teaches that the cells, or subjects, can be irradiated one or more times (page 40, [0444]) and that a single irradiation can be performed to effect activation in order to cause PIT-induced cell killing of tumor cells expressing the immunosuppressive molecule, e.g., PD-L1 (page 46, [0499]). US’405 teaches that activation of the dye-conjugate by irradiation with absorbing light, such as NIR light, excites the photosensitizer and results in cell killing, thereby reducing or eliminating the lesion and treating the disease or condition. In some cases, the use of light in the NIR range leads to deeper tissue penetration resulting in successful eradication of tumors after only a single dose of external NIR light irradiation (page 13, [0206]).
US’405 teaches that a therapeutically effective amount or concentration of the conjugate is one that is sufficient to prevent advancement, such as metastasis, delay progression, or to cause regression of a disease, or which is capable of reducing symptoms caused by a disease, such as cancer. In some embodiments, the methods are sufficient to increase the survival time of the patient with a tumor (page 32, [0388]). US’405 further teaches that in a population of subjects treated with the conjugate, the provided methods result in a complete response (CR) in at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% of the treated subjects (page 50, [0527]). US’405 further teaches that a desired response is increased survival time of a patient with a tumor evident by an increase in one or more survival indicators from among duration of median progression-free survival, duration of response, or median overall survival (page 49, [0522]).
US’405 teaches that the disclosed methods can be used as an initial treatment for cancer either alone, or in combination with radiation or other chemotherapies. The methods can also be used in patients who have failed previous radiation or chemotherapy or who have received other therapies that did not provide a desired therapeutic response or outcome. The disclosed methods can also be used in patients with localized and/or metastatic cancer (page 32, [0382]). As US’405 teaches treatment as an “initial treatment” an ordinarily skilled artisan would reasonably envision that the subject can be naïve to treatment, including with an immune checkpoint inhibitor.
US’405 teaches that the cancer may include metastasis and invasion of surrounding or distant tissues or organs, such as lymph nodes, etc. Metastatic disease may refer to cancer cells that have left the original tumor site and migrated to other parts of the body, for example via the bloodstream or lymph system (page 30, [0367]).
US’405 further teaches anti-cancer agents that can be administered in combination with photoimmunotherapy employing phthalocyanine dye-targeting molecule conjugates including any agent that can reduce, arrest, or prevent cancer in a subject. Optionally, an additional anti-cancer immune modulating agent can be used in combination therapy with the conjugate (page 47, [0500]-[0501]). US’405 teaches that the combination therapy can increase the killing of the tumor cells compared to cell killing in therapy methods using only the conjugate or methods involving a monotherapy with the immune modulating agent or anti-cancer agent alone (page 49, [0521]).
US’405 teaches that the cells are irradiated with a therapeutic dose of radiation at a wave length from within a range of 400 to 900 nm, or 690±50 nm (page 39, [0437]) applied about 30 minutes to about 48 hours after administering the conjugate (page 40, [0443]). US’405 further teaches dosages of 1 to about 1000 J/cm2 including 25, 50, 75, 100, 150, 200, 300, and 400 J/cm2 and 1 J/cm fiber length to 500 J/cm fiber length (page 39, [0438]-[0439]). In some embodiments, the first irradiation with light is provided to the tumor after administration of the first conjugate, for example, from about 12 – 48 hours, such as about or approximately 24 hours after administration of the conjugate. The tumor is treated with light to kill cancer cells that express the immunosuppressive molecule, such as to kill tumor cells that express PD-L1. In some embodiments, the killing of such cancer cells may permit re-activation of or amplification of T cell responses at the tumor (page 46, [0498]).
US’405 further teaches methods of treating a disease or condition including administering a therapeutically effective amount of the conjugate, wherein the conjugate binds to a cell present in the microenvironment or a lesion associated with a disease or condition, and, after administering the conjugate, irradiating the lesion at one or more wavelengths to induce phototoxic activity of the conjugate, thereby treating the disease or condition (pages 11-12, [0156]).
US’405 teaches that the conjugate can be used to treat a lesion, where the lesion is a tumor, and the tumor is cancer including cancer of the head and neck, breast, liver, colon, ovary, prostate, pancreas, brain, cervix, bone, skin, lung, or blood (page 30, [0367]). US’405 further teaches cancers including lymphoma, multiple myeloma, colorectal cancer, non-small cell lung cancer, renal cell carcinoma, and stomach cancer (page 30, [0368]-[0369]).
US’405 further teaches that PD-L1, also known as CD274 and B7-H1, and PD-L2, are ligands for PD1, found on activated T cells, B cells, myeloid cells, macrophages, and some types of tumor cells. Anti-tumor therapies have focused on anti-PD-L1 antibodies. The complexes of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (page 43, [0476]).
US’405 further teaches that the targeting molecule binds to a cell that is a cancer cell, a tumor cell or an immune cell, such as a T cell, a B cell, a natural killer (NK) cell, a dendritic cell, a macrophage, or a neutrophil (page 19, [0266]). US’405 further teaches that, in the case of tumors, the tumor microenvironment has mechanisms to suppress the immune system, thereby evading immune recognition and preventing or reducing killing of tumor cells. For example, in some cases, immune checkpoint proteins can be dysregulated in tumors, thereby resulting in a suppression of the immune response in the tumor microenvironment as a mechanism of evading the immune system. In some cases TIL can include Tregs, which are cells that are capable of suppressing proliferation of other T cells in the microenvironment (pages 19-20, [0271]).
US’405 further teaches that the targeting molecule binds to a cell surface protein on a tumor or cancer cell. In some embodiments, the targeting molecule binds to a cell surface protein on an immune cell or other non-cancerous cell present in a tumor microenvironment. For instance, a cell surface protein on the surface of a T lymphocyte, such as a Treg, a dendritic cell, a NK cell, a B cell, a macrophage or other immune cell that is present in a tumor microenvironment (page 20, [0272]).
US’405 teaches that the phthalocyanine-dye conjugate can be activated by irradiation with near-infrared light. Features of the conjugates, compositions, and methods, including the dose of the conjugate, provide various advantages, such as lower toxicity and/or improved efficacy (abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by Nagaya to substitute the two illuminations taught by Nagaya with one illumination as taught by US’405. It would have been obvious to use one illumination as US’405 demonstrates that the prior art recognized one illumination as an alternative to two illuminations with the use of phthalocyanine-dye conjugates. Additionally, US’405 teaches that the use of light in the NIR range leads to deeper tissue penetration resulting in successful eradication of tumors after only a single dose of external NIR light irradiation. An ordinarily skilled artisan would have had a reasonable expectation of success as both Nagaya and US’405 teach the use of phthalocyanine-dye conjugates, including PD-L1 conjugated with IR700, for the treatment of cancer and US’405 recognizes alternative numbers of illumination as being effective for such treatment.
Regarding claims 6, 8, and 10-12, as discussed in detail above, US’405 teaches that the anti-PD-L1 IR700 conjugate can be used to treat cancer including metastasis invading of surrounding or distant tissues or organs. US’405 teaches that metastatic disease may refer to cancer cells that have left the original tumor cite and migrated to other parts of the body, suggesting that they are phenotypically and/or genotypically the same as the first tumor. US’405 also teaches a variety of cancers that can be treated with the anti-PD-L1 targeting conjugate including many phenotypically/genotypically distinct types of cancer. As US’405 teaches that these types of metastasis/different cancers can be treated with an anti-PD-L1 IR700 conjugate, an ordinarily skilled artisan would reasonably expect that treating the tumor or lesion using the method taught by the combination of Nagaya and US’405 would result in the further inhibition, delay, or prevention in the appearance, growth, or establishment of one or more second tumors located distally to the first tumor or lesion. An ordinarily skilled artisan would have a reasonable expectation of success as both Nagaya and US’405 teach administration of an anti-PD-L1 IR700 conjugate for the treatment of cancer and demonstrate that such conjugate can treat metastatic cancer as well as various types of cancers.
Furthermore, the limitations recited in the claims are mechanistic outcomes that would flow naturally from the method taught by the combination of Nagaya and US’405 in which PD-L1 expressing tumors are treated with an avelumab-IR700 conjugate followed by NAR light exposure.
MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
For instance, Nagaya and US’405 teaches that such administration results in rapid cell death in vitro and tumor growth reduction and survival improvement in vivo. While Nagaya does not explicitly demonstrate that the administration of the conjugate to treat the tumor would result in the further inhibition or delay of the appearance, growth or establishment of one or more second tumors or lesions distally located to the first treated tumor or lesion, this result would flow naturally from administration of the conjugate in the treatment of the initially targeted lesion. That is to say that administration of the conjugate to treat the initial cancer would naturally result in the outcomes claimed for one or more second tumors whether Nagaya and US’405 recognized such outcomes or not. This is particularly the case as no further steps are required for the treatment of such secondary tumors beyond the first initial administration of the conjugate and illumination.
Regarding claim 21, an ordinarily skilled artisan would have reasonably expected that the treatment method taught by the combination of Nagaya and US’405 would delay regrowth or prolong duration of remission based on the teachings of US’405 which teaches that administration of an anti-PD-L1 IR700 conjugate and subsequent illumination can result in complete responses and increase survival indicators such as duration of median progression-free survival, duration of response, or median overall survival.
Regarding claim 29, as discussed in detail above, Nagaya teaches that monoclonal antibodies against PD-L1 and PD-1 have demonstrated clinical benefit with the mode of action of these antibodies being the inhibition of the interaction between PD-1 on immune cells and PD-L1 on tumor cells, thus reducing or eliminating immunosuppressive signals leading to enhanced immune cell activation. Nagaya also teaches that administration of an avelumab IL700 conjugate might be successful in treating cancers that have not responded to the naked antibody alone.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method to treat a subject who had been previously treated with an anti-PD-1 antibody. It would have been obvious to treat this patient population as Nagaya suggests treatment of patients who were treated with a naked anti-PD-L1 antibody which, based on the teachings of Nagaya as a whole, has the same mode of action as anti-PD-1 antibodies, which is the inhibition of the anti-PD-1/PD-L1 pathway. As such, it would have been obvious to treat a subject who had previously been treated with either antibody type with a reasonable expectation of success. The treatment of this patient population is further supported by US’405, which teaches the treatment of patients who have received other therapies that did not provide a desired therapeutic response or outcome.
Regarding claims 34-35, as discussed in detail above, US’405 teaches that the conjugate can target a tumor cell, cancer cell, or an immune cell or other non-cancerous cell present in a tumor microenvironment. For instance, activated T cells, B cells, myeloid cells, macrophages, and some types of tumor cells. Additionally, US’405 teaches that PD-L1 is expressed on these immune cells, indicating that the PD-L1 targeting conjugate in the method taught by Nagaya and US’405 would target such cells based on the use of the PD-L1 antibody in the conjugate. Therefore, one of ordinary skill in the art would reasonably expect that the method would result in the killing of PD-L1 expressing immune cells including myeloid cells and macrophages.
Furthermore, the limitations of claims 34-35 would flow naturally from the administration of the avelumab-IR700 and, therefore, cannot be the basis for patentability when the differences would have otherwise been obvious. See MPEP 2145 II. That is to say that the administration of the anti-PD-L1 IR700 conjugate in the methods of Nagaya and US’405 would naturally find and bind cells that express PD-L1 and, upon NIR light exposure, result in killing of the cells whether Nagaya and US’405 recognized immune cells in addition to the tumor cells or not, and cannot be the basis for patentability when the differences would have otherwise been obvious. See MPEP 2145 II.
Regarding claims 38-39, US’405 further teaches that the complex of PD1 and PD-L1 inhibits proliferation of CD8+ T cells and reduces the immune response (page 43, [0476]). US’405 further teaches that phthalocyanine-dye conjugates containing an immune modulating agent that binds to PD-L1 can be administered to both enhance an immune response and to specific kill cancer cells that express the immunosuppressive molecule, thereby reversing immune suppression in the tumor microenvironment (page 45, [0492]). Based on these teachings, one of ordinary skill in the art would reasonably expect that the method taught by the combination of Nagaya and US’405 would result in an enhanced immune response including increases in the proliferation of CD8+ T cells in the tumor microenvironment.
Furthermore, the claimed increases in the number, level or activity of immune cells in the microenvironment, increases in the number or level of CD8+ T cell infiltration in the tumor or lesion, and/or in the number or level of memory T cells in the vicinity of the tumor or lesion are outcomes that would flow naturally from administration of the conjugate. That is to say that administration of the avelumab-IR700 conjugate would naturally reduce or eliminate immunosuppressive signals leading to enhanced immune activation, as taught by Nagaya and US’405 (page 8807, right column, paragraph 1), which would naturally result in the claimed outcomes whether Nagaya and US’405 recognized them specifically or not, and cannot be the basis for patentability when the differences would have otherwise been obvious. See MPEP 2145 II.
Claims 4, 14, 19, 34-35, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Nagaya, T., et al (2017) Near infrared photoimmunotherapy with avelumab, an anti-programed death-ligand 1 (PD-L1) antibody Oncotarget 8(5); 8807-8817 in view of US 2018/0250405 A1 (Biel, M., et al) 6 SEPT 2018 as applied to claims 1 and 2 and in further view of Tang, F. and P. Zheng (2018) Tumor cells versus host immune cells: whose PD-L1 contributes to PD-1/PD-L1 blockade mediated cancer immunotherapy? Cell Biosci 8(34); 1-8.
It is noted that claims 4, 34-35, and 38-39 were rejected above over the combination of Nagaya and US’405. The claims are further rejected here to further demonstrate that a person of ordinary skill in the art would have reasonably expected the killing of immune cells in the target area, and an increase in the number, level, or activity of immune cells, such as CD8+ T cells, in the tumor or lesions.
The combination of Nagaya and US’405 teaches the methods of claim 1 and 2 as discussed in detail above.
As discussed in detail above, US’405 teaches that the anti-PD-L1-IR700 conjugate targets an immune cell or other non-cancerous cell present in a tumor microenvironment, for instance a T lymphocyte, such as a Treg, a dendritic cell, a NK cell, a B cell, a macrophage, or other immune cell that is present in the tumor microenvironment (page 20, [0272]). US’405 also teaches that such cells express PD-L1 and; therefore, would naturally be targeted by the anti-PD-L1 antibody conjugate taught by Nagaya and US’405.
The combination of Nagaya and US’405, however, does not disclose that that the tumor cell does not express or has a reduced expression of an immune checkpoint protein selected from PD-L1, PD-1, and CTLA-4, or that the tumor comprises PD-L1 negative tumor cells.
Tang teaches that antibody blockade of the PD-1/PD-L1 signaling pathway has elicited durable antitumor responses in the therapy of a broad spectrum of cancers. PD-L1 is constitutively expressed in certain tumors and host immune cells and its expression can be induced or maintained by many factors. The expression of PD-L1 on tumor tissues has been reported to be positively correlated with the efficacy of anti-PD-1/PD-L1 therapy in patients. However, multiple clinical trials indicate that patients with PD-L1 negative tumors also respond to this blockade therapy, which suggests the potential contribution of PD-L1 from host immune cells. Recent to the publication, six articles had independently evaluated and verified the contributions of PD-L1 from tumor versus non-tumor cells in various mouse tumor models. The reports highlight the essential roles of PD-L1 from host myeloid cells in negatively regulating T cell activation and limiting T cell trafficking (abstract). Tang provides an overview of the studies which included tumor cells from sarcoma, colorectal tumors, melanoma, lymphoma, lung cancer, and ovarian cancer (page 3, Table 1).
In studies of ovarian cancer, melanoma, and lung cancer tumor models, it is taught that PD-L1 on tumor cells does not contribute to PD-L1 blockade efficacy, rather, PD-L1 on host DCs and macrophages predicts clinical efficacy to PD-L1 blockade (page 3, Table 1, last row, last column). Tang teaches that, in mice bearing PD-L1 deficient tumors, anti-PD-L1 treatment reduced tumor growth. In the study, a correlation is shown between expression of PD-L1 on dendritic cells (DCs)/macrophages and the efficacy of treatments with either anti-PD-1 alone or in combination with anti-CTLA4. It was concluded that the host immune system is indispensable for PD-1/PD-L1 blockade therapy, and the host DCs and macrophages-derived PD-L1, rather than cancer cell-intrinsic PD-L1, predominantly accounts for blocked therapeutic efficacy (page 4, right column, paragraph 2).
Tang teaches that taken together, the independent studies discussed largely complement and validate each other. The work provided extends the mechanisms of action of PD-1/PD-L1 blockade therapy into the tumor microenvironment and largely supports the concept that PD-L1 acts as a molecular shield on both tumor cells and host immune cells to prevent tumors from cytolysis by T cells. PD-L1 expressed on cancerous cells is not exclusively responsible for the therapeutic effect of PD-1/PD-L1 checkpoint blockade, whereas PD-L1 on both malignant and immune cells works concretely to functionally modulate the CTLs in the tumor microenvironment. Therefore, PD-L1 from both sources could be predictive of sensitivity to therapeutic agents targeting the PD-1/PD-L1 axis (page 6, right column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the method taught by the combination of Nagaya and US’405 to treat tumor cells that do not express PD-L1, or comprises PD-L1 negative tumor cells, based on the teachings of Tang. It would have been obvious to treat tumor cells that are PD-L1 negative as Tang teaches that PD-L1 negative tumors have responded to PD-L1 blockade and that PD-L1 on either tumor cells or host immune cells contribute to tumor escape. The targeting of PD-L1 on immune cells in PD-L1 negative tumors is further supported by US’405, which teaches that the anti-PD-L1 IR700 conjugates can be used to target either tumor cells or immune cells in the tumor microenvironment for the treatment of cancer. As such, a person of ordinary skill in the art would reasonably expect that the avelumab-IR700 conjugate of Nagaya and US’405 would be capable of targeting PD-L1 expressing immune cells in PD-L1 negative tumors thereby treating the tumor. An outcome which is supported by Tang which teaches that even when PD-L1 knockout tumors were used, anti-PD-L1 therapy remained effective. Additionally, Tang teaches studies of lung cancer, which is the same type of cancer taught by Nagaya for treatment with the conjugate. The cancers taught by Tang also overlap with the cancers disclosed by US’405 for treatment with the conjugates.
Regarding claims 4, 34-35, and 38-39, as discussed in detail above, the combination of Nagaya, US’405, and Tang teach administration of an anti-PD-L1 IR700 conjugate for the treatment of cancer and teaches that the conjugate results in specific binding and cell-specific killing after exposure of the cells to NIR in vivo. A person of ordinary skill in the art would have reasonably expected that PD-L1 expressing immune cells in the target area, such as Tregs, macrophages, and dendritic cells, would also be killed based on the teachings of US’405 and Tang, which would result in increases in CD8+ T cell numbers and activity.
As discussed above, both US’405 and Tang teaches that cells such as Tregs, macrophages and dendritic cells in the tumor microenvironment express PD-L1. Based on these teachings, an ordinarily skilled artisan would reasonably expect that administration of the conjugate of Nagaya and subsequent NIR light exposure would act to kill PD-L1 expressing cells which includes Tregs, macrophages, and dendritic cells in the tumor microenvironment. As Tang teaches that PD-L1 directly suppresses activated tumor-infiltrated antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) (page 6, right column, paragraph 1), an ordinarily skilled artisan would reasonably expect that the killing of PD-L1 expressing cells would result in increased numbers and activity of CD8+ T cells in the tumor microenvironment as PD-1/PD-L1 interactions would no longer be suppressing the activated CTLs.
Furthermore, the increase in the number, level, or activity of immune cells and of CD8+ T cell infiltration in the tumor or lesion or the level of memory T cells in the vicinity of the tumor or lesion being increased after treatment are mechanistic results that would flow naturally from following the suggestions of the combination of applied references whether the references explicitly recognized such result or not, and cannot be the basis for patentability when the differences would have otherwise been obvious. See MPEP 2145 II.
Response to Arguments
Applicant’s arguments in the response filed 08/07/2026 have been fully considered, but are not persuasive.
With regards to the rejection of the claims under 35 USC 103, applicant argues that one of ordinary skill in the art would not have been motivated to arrive at the claimed method or have a reasonable expectation of success. Specifically, applicant argues that Nagaya does not identify, characterize, or study tumors that are reduced in susceptibility to treatment with an immune checkpoint inhibitor. Applicant argues that the rejection relies on the statement in Nagaya where it is taught that the NIR-PIT using PD-L1 as the target antigen “might” be successful in cancers that were not previously responsive to the naked antibody alone, but that this statement does not establish a reasonable expectation of success. Applicant argues that clinical benefit discussed in Nagaya was a hypothesis and cites a portion of Nagaya, page 8812, right column, paragraph 3 which teaches that increased expression of PD-L1 could further increase the effects of NIR-PIT through increased numbers of antibody conjugated IR700 molecules on the cell surface. Applicant argues that there is no data or reliable technical basis connecting Nagaya’s demonstrated efficacy in the studied model with the claimed ICI reduced susceptibility population.
This argument is not persuasive.
Although Nagaya does not provide data regarding the treatment of a tumor that has reduced susceptibility to treatment with an immune checkpoint inhibitor, conclusive proof of efficacy is not required in order to establish obviousness. Rather, the standard of obviousness is a reasonable expectation of success. MPEP 2143.02 (I) states “conclusive proof of efficacy is not required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”.
In this case, Nagaya demonstrates the efficacy of avelumab-IR700 in inducing significant therapeutic responses and explicitly states that the NIR-PIT utilizing PD-L1 as the target antigen for the APC might be successful in treating cancers that have not previously responded to the naked antibody alone. Teachings which directly suggest the treatment of the instantly claimed tumor population and provides a reasonable expectation of success, particularly as Nagaya demonstrates efficacy of the conjugate in treating cancers.
Applicant further cites OSI Pharmaceuticals. LLC v. Apotex Inc. and Ex parte Macallister, Appeal 2022003799 (PTAB Dec 21, 2022) for support.
With regards to OSI Pharmaceuticals. LLC v. Apotex Inc., applicant cites the decision as stating that although the asserted references identified erlotinib as a promising compound for its potential use against cancers generally, they lacked efficacy data or another reliable indicator that erlotinib would successfully treat the particular cancer recited in the claim. Applicant argues that the same deficiency is present here because Nagaya does not provide efficacy data.
With regards to Ex parte Macallister, applicant cites the decision as stating that evidence that a drug treated the same symptom in one form of dementia did not establish that it would treat the same symptom in the claimed form of dementia, absent a factual basis connecting the two conditions.
These arguments are not persuasive.
As discussed above, the standard for obviousness is a reasonable expectation of success and conclusive proof of efficacy is not required. Furthermore, the rejection does not rely on teachings from Nagaya that the conjugate may be effective against cancers in general, or in a different type/form of cancer, as is cited in the decisions applicant references. Rather, the rejection relies on specific teachings in Nagaya suggesting use of the conjugate in the claimed patient population to demonstrate obviousness and a reasonable expectation of success.
Applicant further argues that Nagaya uses immunocompetent mice in their studies, which lack functional T cells and that Nagaya attributes treatment to direct killing, not immune related effects. Applicant argues that Nagaya does not model or characterize any mechanism of reduced susceptibility to ICI therapy. Applicant also argues that, with reference to the immune mediated features recited in the dependent claims, Nagaya’s model could not evaluate adaptive immune response. Applicant argues that Nagaya provides no evidence that treatment would increase CD8+ T cell activity or infiltration, generate immune memory, or inhibit unilluminated distal tumors.
It is first noted that, while Nagaya used immunocompetent mice as a model for studying the efficacy of NIR-PIT using avelumab conjugated to IR700DX, Nagaya directly suggests use of the conjugates and methods disclosed in the treatment of tumors in humans. For instance, Nagaya states “Furthermore, NIR-PIT with avelumab IR700 is a promising candidate for the treatment of PD-L1 expressing tumors that could be readily translated to humans.” (abstract). Therefore, Nagaya directly suggests the use of the conjugate in the treatment of humans which would naturally result in the immune related effects that applicant discusses in the response. Additionally, although Nagaya does not model or characterize any mechanism of reduced susceptibility, the instant claims do not require any specific mechanism or cause of the reduced susceptibility. Rather, the claims only require that the tumor cell has reduced susceptibility to treatment with any immune checkpoint inhibitor.
It is also noted that, in so far as dependent claims 14 and 19, which recite that the tumor cell does not express or has a reduced expression of PD-L1, PD-1, and/or CTLA-4 (claim 14) or that the tumor is PD-L1 negative, could be considered a mechanism of resistance; the rejection of these claims does not rely on Nagaya alone and; therefore, Nagaya is not required to individually teach these mechanisms. This is particularly the case as the rejection is based on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art prior to the effective filing date of the claimed invention. See MPEP 2145 (IV). These claims are rejected over the combination of Nagaya, US’405, and Tang and Tang is applied to demonstrate that PD-L1 is also expressed on host immune cells and that patients with PD-L1 negative tumors can also respond to targeted therapy attributed to the contribution of PD-L1 on host immune cells.
With regards to applicant’s arguments that Nagaya’s model does not evaluate adaptive immune response or teach that treatment would increase CD8+ T cell activity/infiltration, generate immune memory, or inhibit unilluminated distal tumors, these outcomes are mechanistic responses that would flow naturally from applying the methods taught by the combination of applied art in humans as is directly suggested by the combination of applied references. As discussed in detail in the rejection, MPEP 2145 II. states that the fact that applicant has recognized another advantage that would flow naturally from following the suggestions of the prior art cannot be the basis for patentability when the differences would have otherwise been obvious.
Additionally, as discussed in the rejections, the mechanistic results claimed would have been expected based on the combined teaching of the applied references. For instance, US’405 teaches that an anti-PD-L1 IR700 conjugate can be used to treat cancer including metastasis invading surrounding or distant tissues or organs. US’405 also teaches that the conjugate can result in complete responses and increase survival indicators including duration of PFS, response, and median overall survival. US’405 also teaches immune cells that would be targeted with the anti-PD-L1 conjugate and also indicates that the conjugate can both enhance an immune response and reverse immune suppression in the tumor environment that inhibits CD8+ T cell proliferation.
Applicant further argues that US’405 (which applicant references as “Biel”) teaches the use of photoimmunotherapy in patients who have failed prior radiation or chemotherapy, which are different than ICI resistance.
Although US’405 does not teach the claimed patient population, US’405 is not required to teach patients who have reduced susceptibility to ICI as this limitation is taught by Nagaya, as discussed in detail above. As discussed above, the rejection is based on a combination of the applied references and what the combination would have suggested to one of ordinary skill in the art.
Applicant further argues that the claimed invention is non-obvious in view of unexpected results. Applicant argues that the applicant demonstrates that phthalocyanine dye conjugates targeting PD-L1 are effective in tumors or lesions with reduced susceptibility to immune checkpoint inhibitors, citing Examples 8-12, 14, and 15. The results referenced by applicant were fully discussed in the office action of 04/09/2026.
The referenced results, however, are not persuasive.
In the examples of the instant disclosure, applicant compares outcomes of anti-PD-L1 PIT with results from controls treated with saline, anti-PDL1-IR700 without illumination, or naked anti-PD-L1 antibody (either as a single or multi dose regimen). These comparisons, however, are not a comparison to the closest prior art, for instance the method of Nagaya, in order to demonstrate that the result is unexpected or to demonstrate the criticality of any of the claimed elements.
MPEP 716.02 (b)(III) states “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.” MPEP 716.02 (e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
Additionally, the results presented would have been expected in view of the teachings of the prior art. MPEP 716.02 states “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”
An ordinarily skilled artisan would have reasonably expected the results presented in the instant disclosure based on the combined teachings of Nagaya and US’405 as well as Nagaya, US’405, and Tang. For instance, Nagaya demonstrates that anti-PD-L1-IR700 conjugates with NIR can be used to treat cancer and predicts that such conjugate could be used to treat cancers that are not responsive to anti-PD-L1 antibodies alone. US’405 also teaches the use of anti-PD-L1-IR700 conjugates in the treatment of cancers and suggests that one or more illuminations would be effective in treating cancers. US’405 also establishes that PD-L1 is expressed on immune cells in the tumor microenvironment and that such immune cells can be targeted with the conjugates. Tang teaches that, in PD-L1 negative tumors, immune cells in the tumor microenvironment can still effectively be targeted to treat the cancer. As such, one of ordinarily skilled artisan would have reasonably expected that the anti-PD-L1 conjugate with PIT studied by applicant would result in the outcomes that are demonstrated.
Furthermore, as discussed in detail in the rejection and response above, mechanistic outcomes demonstrated by applicant that would flow naturally from following the suggestions of the prior art cannot be the basis of patentability when the differences would have otherwise been obvious. Additionally, "The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.” See MPEP 2145 II.
Furthermore, even if the results presented were unexpected, which they are not, the results are not commensurate in scope with the claimed invention. MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
The independent claims of the instant invention encompass any phthalocyanine dye linked to any targeting molecule that binds to PD-L1 at any concentration and are used to treat any tumor that is reduced in susceptibility to treatment with any immune checkpoint inhibitor. The examples of the instant disclosure, which applicant argues results in unexpected outcomes, demonstrates only a single conjugate, specifically an antibody conjugate in which the phthalocyanine dye IR700 is linked to the anti-PD-L1 antibody 10F.9G2 and demonstrates the results at a single concentration of the conjugate, specifically 100 μg. The examples do not demonstrate that the supposedly unexpected property occurs over the full scope of the claimed invention and; therefore, the claims are not commensurate in scope with the results provided.
With regards to this response, which was provided in the office action of 04/09/2026, applicant disagrees that the results are not commensurate in scope with the claimed invention. Applicant argues that the claims do not merely recite any anti-PD-L1 conjugate for any use, but rather a defined therapeutic method with conjugate components, patient population, treatment protocol and outcome. Applicant specifically focuses on antibody 10F.9G2 used in the examples as being representative of the genus of anti-PD-L1 antibodies recited in the claim.
In this case, while it would be expected that any anti-PD-L1 antibody would target PD-L1, as discussed by applicant in the response, the claims do not only present a genus of antibodies, but rather a genus of conjugates which also encompasses any phthalocyanine dye. The examples of the disclosure; however, only demonstrate a single conjugate that has the PD-L1 antibody conjugated to IR700 and demonstrates the results only at a single dosage amount of the conjugate.
It is noted that applicant does not provide any specific response concerning the comparison to the closest prior art or the expectations from the prior art that are discussed above, and were discussed in the response of 04/09/2026, concerning the supposed unexpected results that are presented.
With regards to Tang, applicant argues that Tang is concerned with checkpoint blockade, not ablation of PD-L1 expressing cells and does not establish that destroying the immune cell with the anti-PD-L1 phototoxic conjugate would provide the same results. Applicant further argues that the applied references do not establish that the proposed treatment would successfully treat an ICI-reduced-susceptibility tumor. Applicant specifically argues that this is because Tang’s results arose from blocking PD-L1 not killing them. Applicant also argues that Tang does not supply the claimed tumor population. Tang reports that the tumors lacking tumor-cell PD-L1 remained responsive to PD-1/PD-L1 blockade because PD-L1 was expressed by host cells.
These arguments are not persuasive.
It is first noted that the independent claim only requires that the tumor cells have “reduced susceptibility to treatment with an immune checkpoint inhibitor”. The claim does not require that there be no response nor does the claim require any degree of reduced susceptibility.
That said, Tang is applied in combination with Nagaya and US’405 in order to demonstrate that it would have been obvious to apply the method taught by the combination of references in PD-L1 negative tumors with a reasonable expectation of success. Tang is not required to teach the claimed patient population as this limitation is met by the teachings of Nagaya which, as discussed above, directly suggests that anti-PD-L1-IR700 conjugates might be successful in treating cancers that have not previously responded to the naked antibody alone.
Additionally, with regards to the outcomes of Tang, such as the increase in CD8+ T cell activity, as discussed above, while these limitations would have been reasonably expected by the teachings of the combination of applied references, they are also mechanistic outcomes that would flow naturally from following the suggestions of the prior art and cannot be the basis for patentability when the differences would have otherwise been obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Copending application 17/469,804
Claims 1-6, 8, 10-12, 14, 19, 21, 23-24, 29, 31, 34-35, 38-39, 43, 49-51, 55, and 58-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 209-230 and 232-234 of copending Application No. 17/469,804 in view of Nagaya, T., et al (2017) Near infrared photoimmunotherapy with avelumab, an anti-programed death-ligand 1 (PD-L1) antibody Oncotarget 8(5); 8807-8817, Tang, F. and P. Zheng (2018) Tumor cells versus host immune cells: whose PD-L1 contributes to PD-1/PD-L1 blockade mediated cancer immunotherapy? Cell Biosci 8(34); 1-8, and US 2018/0250405 A1 (Biel, M., et al) 6 SEPT 2018.
App’804 claims a phototoxic conjugate comprising at least one silicon phthalocyanine dye conjugated to a targeting molecule that binds PD-L1 (claim 209); wherein the targeting molecule that binds PD-L1 is an anti-PD-L1 antibody or antigen binding fragment thereof (claims 210 and 233) and is selected from among MDX-1105, MEDI4736, AMP224, BMS-936559, MPLDL3280A, MSB0010718C, and antigen binding fragments thereof (claims 211 and 234). App’804 claims that the silicon phthalocyanine dye is RI700 (claims 212-213 and 232). Further claimed is pharmaceutical compositions for treating a tumor comprising the conjugate an a pharmaceutically acceptable carrier (claim 214) and that the conjugate exhibits phototoxicity upon illumination to kill an immune cell expressing PD-L1 in the microenvironment of the tumor (claims 215 and 229). App’804 claims that the immune cell is a T cell, a B cell, a myeloid cell, or a macrophage (claims 216 and 230) and that the illumination enhances the immune response in a subject (claims 217 and 231). App’804 claims that the phototoxicity inhibits the growth of a tumor (claim 218).
App’804 further claims a method of treating a lesion comprising administering a conjugate comprising a silicon phthalocyanine dye conjugated to a PD-L1 targeting molecule and, after, irradiating the lesion at a wave length of 690±50 nm at a dose of at or about 50-100 J cm-2 or at or about 100 J/cm of fiber length, thereby treating the lesion (claim 219). App’804 claims that the irradiation is carried out between 30 minutes and 96 hours after administering the phototoxic conjugate, and 24 hours ± 3 hours after administration of the conjugate (claims 220-221). App’804 further claims that the wavelength is 690±20 nm (claim 222) and that the dose is at or about 50 J cm-2 or at or about 100 J/cm fiber length (claim 223). App’804 claims that the conjugate is administered intravenously or as an injection (claim 224). App’804 claims that the method of claim 219 can be repeated in a dosing schedule (claim 226) and that the dosing schedule is repeated if a residual lesion remains at a time that is more than or is about 2, 3, or 4 weeks, or 2 or 6 months, or 1 year after initiation of the prior administration of the conjugate (claim 226). App’804 claims that the irradiating step is carried out using a microlens-tipped fiber for surface illumination or using one or more cylindrical diffusing fibers (claim 227). App’804 claims that the lesion is associated with a disease selected from the group consisting of bladder cancer, stomach cancer, lung cancer, colon cancer, head and neck cancer, breast cancer, an endometrial cancer, and a pancreatic cancer (claim 228).
The claims of App’804 differ from those of the instant claims in that the claims of App’804 does not limit the tumor or lesion treated to comprising a tumor cell that is reduced in susceptibility to treatment with an immune checkpoint inhibitor or that the method results in the reduction or inhibition of the growth, size, or viability of the tumor or lesion. App’804 also does not claim that the tumor or lesion does not express PD-L1 or is a PD-L1 negative tumor, that the subject is naïve to treatment with a checkpoint inhibitor or that the method further comprises administering an additional agent.
The teachings of Nagaya, Tang, and US’405 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’804 to treat a tumor cell that is reduced in susceptibility to treatment with an immune checkpoint inhibitor based on the teachings of Nagaya. A person of ordinary skill in the art would have been motivated to include treatment of this patient population in the methods of App’804 as Nagaya teaches that administration of an anti-PD-L1 IR700 conjugate could be successful in treating cancers that have not previously responded to the naked antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as, like App’804, Nagaya teaches a method in which an anti-PD-L1 IR700 conjugate is administered to treat cancer followed by irradiation with the same wavelength and dose of the claims of App’804. One of ordinary skill in the art would reasonably expect that the method would result in rapid cell death in vitro and tumor growth reduction and survival improvement in vivo as Nagaya teaches such outcomes were observed with anti-PD-L1 IR700 conjugates.
It would have been prima facie obvious to one of ordinary skill in the art to apply the method methods of App’804 to treat tumor cells that do not express PD-L1, or comprises PD-L1 negative tumor cells, based on the teachings of Tang. It would have been obvious to treat tumor cells that are PD-L1 negative as Tang teaches that PD-L1 negative tumors have responded to PD-L1 blockade and that PD-L1 on either tumor cells or host immune cells contributes to tumor escape. As such, a person of ordinary skill in the art would reasonably expect that the anti-PD-L1 IR700 conjugate of App’804 would be capable of targeting PD-L1 expressing immune cells in PD-L1 negative tumors thereby treating the tumor. An outcome which is supported by Tang which teaches that even when PD-L1 knockout tumors were used, anti-PD-L1 therapy remained effective. Additionally, Tang teaches studies of cancers overlapping with the types of cancers claimed by App’804 for treatment with the conjugate.
It would have further been obvious to treat a subject who is naïve to treatment with an immune checkpoint inhibitor as US’405 teaches that methods using anti-PD-L1 IR700 conjugates can be used as an initial treatment for cancer, indicating that subjects who can be treated with conjugates such as those claimed by App’804 can include those who have not received any prior treatment, which would include a checkpoint inhibitor. An ordinarily skilled artisan would have been motivated to further administer an additional anti-cancer agent as US’405 teaches that additional agents can increase the killing of the tumor cells compared to cell killing in therapy methods using only the conjugate or methods involving a monotherapy with the immune modulating agent or anti-cancer agent alone. An ordinarily skilled artisan would reasonably expect that the method of App’804 would result in prolonged duration of remission based on the teachings of US’405 which teaches that administration of an anti-PD-L1 IR700 conjugate can increase survival indicators such as duration of median progression-free survival, duration of response, or median overall survival and that the treatment can result in complete remission (page 50, [0527]). An ordinarily skilled artisan would have had a reasonable expectation of success as both App’804 and US’405 teach anti-PD-L1 IR700 conjugates for the treatment of cancer. Additionally, the references teach overlapping cancers that can be treated by targeting PD-L1, such as lung cancer, melanoma, and lymphoma.
Regarding claims 6, 8, 10-12, and 38-39, the limitations recited in the claims are mechanistic outcomes that would flow naturally from the method claimed by App’804 in which PD-L1 expressing tumors are treated with an anti-PD-L1 IR700 conjugate followed by NAR light exposure. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Additionally, these results would have been expected based on the teachings of Nagaya, Tang, and US’405 for the reasons discussed in detail in the rejections under 35 USC 103 above.
This is a provisional nonstatutory double patenting rejection.
Copending application 18/838,585
Claims 1-6, 8, 10-12, 14, 19, 21, 23-24, 29, 31, 34-35, 38-39, 43, 49-51, 55, and 58-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-23, 25-27, 45, 52, and 64 of copending Application No. 18/838,585 in view of Nagaya, T., et al (2017) Near infrared photoimmunotherapy with avelumab, an anti-programed death-ligand 1 (PD-L1) antibody Oncotarget 8(5); 8807-8817, Tang, F. and P. Zheng (2018) Tumor cells versus host immune cells: whose PD-L1 contributes to PD-1/PD-L1 blockade mediated cancer immunotherapy? Cell Biosci 8(34); 1-8, and US 2018/0250405 A1 (Biel, M., et al) 6 SEPT 2018.
The claims of App’585 encompasses a conjugate comprising a PD-L1 antibody (the antibody of claim 1) and a heterologous molecule or moiety, where the heterologous molecule or moiety is a photoactivatable dye (claims 21-23 and 64). App’585 further claims that the photoactivatable dye is a Si-phthalocyanine dye, including IR700 (claims 26-27). App’585 claims a method of treating a tumor or lesion in a subject in need thereof comprising administering to the subject the conjugate and illuminating the area within the subject with a wavelength of between at or about 600 nm and at or about 850 nm, and at a dose of from or about 25 J/cm2 to at or about 400 J/cm2 or from at or about 2 J/cm fiber length to at or about 500 J/cm fiber length, thereby activating the conjugate; whereby the growth, volume or dimension of the tumor or lesion is reduced or inhibited (claim 45). App’585 further claims a method of immunizing a subject having a first tumor or lesion comprising the above method wherein the first tumor or lesion is inhibited in growth and/or reduced in size and the appearance, growth or establishment of one or more second tumors of lesions, located distally to the treated first tumor or lesion, is inhibited, delayed or prevented (claim 52).
The claims of App’585 differ from those of the instant claims in that the claims of App’585 does not limit the tumor or lesion treated to comprising a tumor cell that is reduced in susceptibility to treatment with an immune checkpoint inhibitor. App’585 also does not claim that the tumor or lesion does not express PD-L1 or is a PD-L1 negative tumor, that the subject is naïve to treatment with a checkpoint inhibitor or that the method further comprises administering an additional agent.
The teachings of Nagaya, Tang, and US’405 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’585 to treat a tumor cell that is reduced in susceptibility to treatment with an immune checkpoint inhibitor based on the teachings of Nagaya. A person of ordinary skill in the art would have been motivated to include treatment of this patient population in the methods of App’585 as Nagaya teaches that administration of an anti-PD-L1 IR700 conjugate could be successful in treating cancers that have not previously responded to the naked antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as, like App’585, Nagaya teaches a method in which an anti-PD-L1 IR700 conjugate is administered to treat cancer followed by irradiation with the same wavelength and dose of the claims of App’585.
It would have been prima facie obvious to one of ordinary skill in the art to apply the method methods of App’585 to treat tumor cells that do not express PD-L1, or comprises PD-L1 negative tumor cells, based on the teachings of Tang. It would have been obvious to treat tumor cells that are PD-L1 negative as Tang teaches that PD-L1 negative tumors have responded to PD-L1 blockade and that PD-L1 on either tumor cells or host immune cells contributes to tumor escape. As such, a person of ordinary skill in the art would reasonably expect that the anti-PD-L1 IR700 conjugate of App’585 would be capable of targeting PD-L1 expressing immune cells in PD-L1 negative tumors thereby treating the tumor. An outcome which is supported by Tang which teaches that even when PD-L1 knockout tumors were used, anti-PD-L1 therapy remained effective.
It would have further been obvious to treat a subject who is naïve to treatment with an immune checkpoint inhibitor as US’405 teaches that methods using anti-PD-L1 IR700 conjugates can be used as an initial treatment for cancer, indicating that subjects who can be treated with conjugates such as those claimed by App’585 can include those who have not received any prior treatment, which would include a checkpoint inhibitor. An ordinarily skilled artisan would have been motivated to further administer an additional anti-cancer agent as US’405 teaches that additional agents can increase the killing of the tumor cells compared to cell killing in therapy methods using only the conjugate or methods involving a monotherapy with the immune modulating agent or anti-cancer agent alone. An ordinarily skilled artisan would reasonably expect that the method of App’585 would result in prolonged duration of remission based on the teachings of US’405 which teaches that administration of an anti-PD-L1 IR700 conjugate can increase survival indicators such as duration of median progression-free survival, duration of response, or median overall survival and that the treatment can result in complete remission (page 50, [0527]). An ordinarily skilled artisan would have had a reasonable expectation of success as both App’585 and US’405 teach anti-PD-L1 IR700 conjugates for the treatment of cancer.
Regarding claims 6, 8, 10-12, and 38-39, the limitations recited in the claims are mechanistic outcomes that would flow naturally from the method claimed by App’585 in which tumors are treated with an anti-PD-L1 IR700 conjugate followed by NAR light exposure. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Additionally, these results would have been expected based on the teachings of Nagaya, Tang, and US’405 for the reasons discussed in detail in the rejections under 35 USC 103 above.
This is a provisional nonstatutory double patenting rejection.
Copending application 18/554,414
Claims 1-6, 8, 10-12, 14, 19, 21, 23-24, 29, 31, 34-35, 38-39, 43, 49-51, 55, and 58-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 152-170 of copending Application No. 18/554,414 in view of Nagaya, T., et al (2017) Near infrared photoimmunotherapy with avelumab, an anti-programed death-ligand 1 (PD-L1) antibody Oncotarget 8(5); 8807-8817, Tang, F. and P. Zheng (2018) Tumor cells versus host immune cells: whose PD-L1 contributes to PD-1/PD-L1 blockade mediated cancer immunotherapy? Cell Biosci 8(34); 1-8, and US 2018/0250405 A1 (Biel, M., et al) 6 SEPT 2018.
App’414 claims a conjugate comprising a silicon phthalocyanine dye covalently linked to a targeting molecule, where the dye has the recited structure. App’414 further claims that the targeting molecule binds to targets including PD-L1. App’414 claims a pharmaceutical composition comprising the conjugate as well as a method of treating a disease comprising administration of the conjugate and, after, illuminating a target region of the subject with an effective dose of light at a wavelength between 660 nm and 690 nm, and wherein the wavelength is 675 nm ± 10 nm. App’414 further claims that the condition is cancer selected from a group which overlaps with those of the instantly claimed invention. App’414 further claims administering an additional therapeutic agent.
The claims of App’414 differ from those of the instant claims in that the claims of App’414 does not limit the tumor or lesion treated to comprising a tumor cell that is reduced in susceptibility to treatment with an immune checkpoint inhibitor or the claimed dose. App’414 also does not claim that the tumor or lesion does not express PD-L1 or is a PD-L1 negative tumor, that the subject is naïve to treatment with a checkpoint inhibitor.
The teachings of Nagaya, Tang, and US’405 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’414 to treat a tumor cell that is reduced in susceptibility to treatment with an immune checkpoint inhibitor and using the claimed dosages based on the teachings of Nagaya. A person of ordinary skill in the art would have been motivated to include treatment of this patient population in the methods of App’414 as Nagaya teaches that administration of an anti-PD-L1 IR700 conjugate could be successful in treating cancers that have not previously responded to the naked antibody alone. An ordinarily skilled artisan would have had a reasonable expectation of success as, like App’414, Nagaya teaches a method in which an anti-PD-L1 IR700 conjugate is administered to treat cancer followed by irradiation with the same wavelength of the claims of App’414.
It would have been prima facie obvious to one of ordinary skill in the art to apply the method methods of App’414 to treat tumor cells that do not express PD-L1, or comprises PD-L1 negative tumor cells, based on the teachings of Tang. It would have been obvious to treat tumor cells that are PD-L1 negative as Tang teaches that PD-L1 negative tumors have responded to PD-L1 blockade and that PD-L1 on either tumor cells or host immune cells contributes to tumor escape. As such, a person of ordinary skill in the art would reasonably expect that the anti-PD-L1 IR700 conjugate of App’414 would be capable of targeting PD-L1 expressing immune cells in PD-L1 negative tumors thereby treating the tumor. An outcome which is supported by Tang which teaches that even when PD-L1 knockout tumors were used, anti-PD-L1 therapy remained effective.
It would have further been obvious to treat a subject who is naïve to treatment with an immune checkpoint inhibitor as US’405 teaches that methods using anti-PD-L1 IR700 conjugates can be used as an initial treatment for cancer, indicating that subjects who can be treated with conjugates such as those claimed by App’414 can include those who have not received any prior treatment, which would include a checkpoint inhibitor. An ordinarily skilled artisan would have been motivated to further administer an additional anti-cancer agent as US’405 teaches that additional agents can increase the killing of the tumor cells compared to cell killing in therapy methods using only the conjugate or methods involving a monotherapy with the immune modulating agent or anti-cancer agent alone. An ordinarily skilled artisan would reasonably expect that the method of App’414 would result in prolonged duration of remission based on the teachings of US’405 which teaches that administration of an anti-PD-L1 IR700 conjugate can increase survival indicators such as duration of median progression-free survival, duration of response, or median overall survival and that the treatment can result in complete remission (page 50, [0527]). An ordinarily skilled artisan would have had a reasonable expectation of success as both App’414 and US’405 teach anti-PD-L1 silicon phthalocyanine dye conjugates for the treatment of cancer.
Regarding claims 6, 8, 10-12, and 38-39, the limitations recited in the claims are mechanistic outcomes that would flow naturally from the method claimed by App’414 in which tumors are treated with an anti-PD-L1 IR700 conjugate followed by NAR light exposure. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Additionally, these results would have been expected based on the teachings of Nagaya, Tang, and US’405 for the reasons discussed in detail in the rejections under 35 USC 103 above.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments in the response filed 08/07/2026 regarding the rejections under nonstatutory double patenting have been fully considered but are not persuasive.
With regards to copending applications App’804, App’585 and App’414, applicant argues that in contrast to the claims of the copending applications, the instant applicant is drawn to a method of treating a specifically defined patient population. Applicant argues that the copending applications do not render the instant claims obvious because they do not characterize, identify, or address this patient population. Applicant also argues that Nagaya, US’405, and Tang also fail to establish a reasonable expectation of success for the reasons discussed above.
This argument is not persuasive.
Although App’804, App’585 and App’414 do not specifically claim the instantly claimed method and recited patient population, the rejection is based on nonstatutory double patenting and; therefore, the copending applications are not required to claim each and every limitation of the instant application in order to be a patentably indistinct variation of the instant claims.
MPEP 1504.06 states “the "nonstatutory" double patenting rejection based on a judicially created doctrine grounded in public policy and which is primarily intended to prevent prolongation of the patent term by prohibiting claims in a second patent not patentably distinct from claims in a first patent. The doctrine of nonstatutory double patenting also seeks to prevent the possibility of multiple suits against an accused infringer by different assignees of patents claiming patentably indistinct variations of the same invention. In re Van Ornum, 686 F.2d 937, 944-48, 214 USPQ 761, 767-70 (CCPA 1982). The submission of a terminal disclaimer in compliance with 37 CFR 1.321(b) to overcome a double patenting rejection ensures that a patent owner with multiple patents claiming obvious variations of one invention retains all those patents or sells them as a group. Van Ornum, 686 F.2d at 944-45, 214 USPQ at 767.”
As discussed in detail in the rejections, the instant claims are obvious variants of the copending applications based on the teachings of Nagaya, US’804, and Tang.
Additionally, applicant’s arguments concerning Nagaya, US’804, and Tang are not persuasive for the reasons discussed in detail above.
With regards to App’585 applicant also argues that the instant application has an earlier term filing date and cites MPEP 804 I.B.1. as saying that when the provisional nonstatutory double patenting rejection is the only remaining rejection it should be withdrawn.
As the provisional nonstatutory double patenting rejection over App’585 is not the only remaining rejection, the rejection is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
